title: Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program.
abstract: BACKGROUND
  IMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent).
  
  
  METHODS
  IMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 µM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated.
  
  
  RESULTS
  Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models.
  
  
  CONCLUSIONS
  IMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined.
authors.affiliation: Hematology-Oncology Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Wood
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.forename: Kathleen
authors.initials: K
authors.lastname: Whiteman
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C579429:lorvotuzumab mertansine; D008453:Maytansine
keywords: antibody-maytansinoid conjugate; developmental therapeutics; microtubules; preclinical testing